International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


IDENTIFICATION OF QTL DETERMINANTS OF TYPE 2 DIABETES SUBPHENOTYPES IN MICE

Ayo Toye
Diabetes QTL and Modifier Loci Group
Medical Research Council
Harwell Nr Didcot
Oxfordshire OX11 0RD UK

Co-Authors: Goldsworthy M, Bentley L, Moir L, Ritson D, Haynes A.E, Mijat V, Cox R.
Institutions: Diabetes QTL and Modifier Loci Group, Medical Research Council

Our aim is to identify novel genes that contribute to glucose regulation and its pathologies including impaired glucose tolerance and type 2 diabetes in humans and other mammals.

Our approach uses a whole genome mapping approach to identify mouse loci that cosegregate with and by implication determine two biochemical phenotypes (plasma glucose and plasma insulin levels) that are perturbed in diabetes. We surveyed 4 inbred mouse strains (C57BL/6J, C3H, DBA/2 and BALB/C) for variation in glucose tolerance during an intraperitoneal glucose tolerance test. We observed larger strain differences in male than female mice. Male C57BL/6J mice were significantly less glucose tolerant than other strains (N=20, P<0.000001). In order to map the underlying genes, we produced an F2 intercross cohort of 700 male and female mice from reciprocal crosses between C57BL/6J and C3H parents then their F1 progeny. F1 males (N=75) were significantly (P<0.0001) different from C57BL/6J (N=20) but not C3H parents (N=20). Glucose tolerance was positively skewed in F2 males (N=350), and about 25% appeared like their C57BL/6J grandparents. To date, we have genotyped mice in the top 17.5% of the F2 glucose tolerance phenotype distribution, and have identified 4 distinct loci that contribute significantly (P<0.00001) to glucose tolerance. We are currently genotyping the remaining 82.5% of the phenotype distribution in order to exploit their full information content.


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